The dietary sodium recommendation by the Institute of Medicine is intended as a `one size fits all' recommendation, but it is becoming clear that each individual is genetically programmed with a personal index of salt sensitivity' and dietary salt (NaCl) consumption guidelines should be personalized. The kidney is a key, but not exclusive, regulator of sodium balance. Within the kidney the anti-natriuretic (sodium retaining) angiotensin type 1 receptor (AT1R) is a dominant regulator of blood pressure homeostasis under conditions of low and normal sodium intake. However, with moderate increase in sodium intake the D1-like dopamine receptors (D1 receptor (D1R) and D5 receptor (D5R)) in conjunction with the angiotensin type 2 receptor (AT2R) exert important counter regulatory natriuretic roles. These counter regulatory processes and end effectors become unbalanced in the presence of variant genes, including those regulating the activity of receptors (such as the G protein-coupled kinase type 4 (GRK4)), second messengers, ion transporters (e.g., sodium bicarbonate cotransporters), and ion exchangers and pumps. This PPG will test the hypothesis that the electrogenic sodium bicarbonate cotransporter NBCe2 (coded by the gene SLC4A5) and GRK4 variant 65L are involved in the etiology of salt sensitivity, a condition affecting 51% of hypertensives and 26% of normotensives. The hypothesis is based on genetic data demonstrating a strong association between variants in SCL4A5 and GRK4-65L and salt sensitivity, as well as preliminary data showing a renal dopaminergic and angiotensin system imbalance and aberrant expression and activity of NBCe2 and the chloride bicarbonate exchanger putative anion exchanger 1 (PAT-1). We will test our hypothesis using human renal proximal and distal tubule cells to examine receptors, transporters, and epigenetic regulatory mechanisms (Project 1). Project 3 will use genetically modified rodents to study the physiology of the same receptors, transporters, and epigenetic pathways as Project 1. Finally, Project 2 will perform in human subjects, expressing various genotypes of SLC4A5 and GRK4, electrolyte balance studies under various manipulations of sodium balance and the dopaminergic and renin-angiotensin systems. This Program Project will yield a thorough understanding of salt sensitivity that affects up to 34% of 58 million Americans.